The development of siRNA cancer therapeutics has been impeded by its inadequate delivery and transfection in solid tumors in vivo. This is due to their unfavorable physicochemical properties, instability and rapid elimination or entrapment in the reticuloendothelial system (RES), lysosomal degradation, and toxicity. Some of these problems can be overcome by structural modifications of RNA and by using stealth nano carriers that improve the stability and reduce the RES-entrapment and toxicity. The two remaining problems are the inability to reach tumor cells located distal to blood vessels and the inability to achieve sufficient transfection. We have obtained preliminary results indicating that certain combinations of chemotherapy and siRNA loaded in a pegylated cationic lipid carrier yielded significant target protein knockdown and therapeutic synergy in animals bearing several types of solid tumors. The goals of this project are to determine the mechanisms of in vivo synergy and to translate these findings into potentially useful chemo-siRNA therapy. The proposed studies are expected to improve the understanding of the barriers to siRNA delivery and transfection in solid tumors in vivo and indicate paths to overcome these major impediments, while translational studies will build on this information to develop optimal chemo-siRNA therapy regimens for clinical evaluation. If successful, the studies will lead to the development of effective chemo-siRNA therapies with broad applications.